Lecture 11: Nonsteroidal Anti-Inflammatory Drugs (Exam 2) Flashcards
What is the MOA of NSAIDs
Blocks the cellular expression of COX enzymes in cell membrane
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What is the response to tissue death
Inflammation
What is the first step in the inflammatory cascade
Release of arrachidonic acid (AA) that is mediated by phospholipase A2 (from injured cell membrane)
What do AAs generate
Various eicosanoids like PGs, leukotrienes, & thromboxane A2)
What mediates the production of PGs & TXA2
COX
What do inflammatory mediators lead to
- Increased vascular permeability
- Heat
- Decreased nociceptor threshold
Describe COX-1
- Primary constitutive isoform of COX
- Responsible for basal prostaglandin (pG) production which helps w/ homeostasis in tissues
- Present in the stomach, kidneys, platelets, & the repro tract
- Can be expressed @ the site of inflammation
Describe COX-2
- Induced isoform of COX
- Expressed constitutively in many tissues like neural, repro, & renal
- Has homeostatic function
T/F: COX has a bifunctional role depending on the isoform & target tissue
True
What tissue do NSAIDs work
- CNS
- Peripheral tissue injury sites
What happens when there is inhibition of COX-2 enzyme peripherally blocks the formation of PGs
- Dilates arterioles
- Sensitize peripheral nociceptors to inflammatory mediators (like histamine & bradykinin)
- Produces localized pain & hypersensitivity
What happens to COX-2 when there is traumatic injury & peripheral inflammation in the brain & spinal cord? Then what ha
- Is upregulated
- Neuronal plasticity & central sensitization due to lowering of the threshold for neuronal depolarization
How does PGE2 contribute to inflammatory response
Causes vasodilation & enhancing inflammatory mediators & other cytokines
What mediates the production of PGE2
COX-2
Why do we no longer use drug therapy to target inhibition of COX-2
B/c COX-2 inhibition is detrimental to many normal physiologic functions like gastric ulcer healing
What is the COX-1: COX-2 selectivity ratio
Varies btw/ species
Describe Coxibs
- Subset of NSAIDs developed to have anti-inflammatory effects but reduced toxicity
- COX-2 selective
- COX-1 sparing
- Structured diff so it limits their ability to bind the COX-1 site
What are the 4 coxibs approved for use in animals
- Deracoxib
- Firocoxib
- Mavacoxib
- Robencoxib
What is the PK of most NSAIDs
- Lipid soluble
- Weak organic acids
- Well absorbed following oral admin
- Rapid onset of action
- Duration of effect can be up to 24 hrs
- Small vol of distribution attributable to a high degree of plasma protein binding (enables consistent delivery to target tissue
- Extensive hepatic metabolism to inactive metabolites
- Elimination 1/2 life if variable
Describe the clinical use of NSAIDs
- Only use one NSAID @ a time
- Baseline renal & hepatic fxn prior to use
- Pay attention to dosages, frequency, & offer it with food
- Use lowest effective dose for the shortest duration possible
- 5 - 7 D “wast out” period if switching NSAIDs
When should NSAIDs not be given
- Renal or hepatic insufficiency/impairment
- Active GI disease
- Coagulopathies
- Pregnant/trying to get preg
- Decreased circulating vol
- Active hemorrhage or suspected blood loss
- Significant pulmonary disease
- known sensitivity of NSAIDs
- Currently receiving systemic steroids or other NSAIDs
What are the 9 ways to min risk w/ NSAIDs
- Obtain complete medical hx
- Careful px selection
- Provide verbal & written instruction
- Recognize adverse events & discontinue immediately
- Monitor labwork
- Use a balanced approach to analgesia
- Consider washout periods
- Consider gastroprotectants
- Dose optimization based on lean body wght
What is a critical step that needs to be done when prescribing NSAIDs
Pet owners need to be told what the possible side effects are & their clinical sxs
Describe carprofen
- COX-1 sparing
- COX-2 selective
- Approved to treat pain & inflammation due to OA & ortho & soft tissue sx in dogs
- Scored caplet or chewable tab can be given PO
- Injectable formulation of 50 mg/ml given SQ
- Long-term use & efficacy carprofen in dogs
What is the major side effect of carprofen
GI upset
Describe on Deracoxib
- COX-1 sparing
- COX-2 selective
- Approved oral formulation for dogs for tx of pain & inflammation assoc w/ OA & postop pain due to ortho sx
- Effective for pain due to dental or soft tissue px
What are the major side effects deracoxib
GI complications like perforations of an ulcer usually related to higher doses
Describe Firocoxib
- COX-1 sparing
- COX-2 selective
- Approved as an oral formulation for the tx of pain & inflammation associated w/ OA in dogs
- Effective for postop pain control
- Injectable & oral paste approved for SID use in the treatment of equine OA
What are the side effects of Firocoxib
- Minimal
- GI upset
Describe Meloxicam
- COX-1 sparing
- COX-2 selective
- Approved for use in dogs for tx of pain & inflammation assoc w/ OA
- Approved for use in cats but only for a single dose to control pain & inflammation assoc w/ ortho surgery, OHE, & castration
- Ava oral, transmucosal oral mist, & parenteral formulas
What is the black box warning label for meloxicam say
Acute renal failure & death assoc w/ repeated use of meloxicam in cats
What are the side effects of meloxicam
GI upset
Describe Robenacoxib
- COX-1 sparing
- COX-2 selective
- Approved for use in dogs & cats for the tx of pain & inflammation associated w/ OA, ortho sx, & soft tissue sx
- Approved tx time in cats less than 4 M is 3 days
- Good safety profile in young healthy cats
- SQ injection
Describe Grapiprant (galliprant)
- Non-COX-inhibiting prostaglandin receptor antagonist (PRA)
- Approved for tx of pain & inflammation in dogs w/ OA
- Doesn’t inhibit the production of many housekeeping prostanoids that maintain homeostatic fxn
- Specifically blocks the EP4 receptor
What is the primary mediator of canine OA pain & inflammation
EP4 receptor
T/F: Acetaminophen is not an NSAID
True
What is acetaminophen used for
Used in humans for antipyretic & analgesic props w/ reduced risk of GI ulceration. Lacks anti-inflammatory props
Why are cats more sensitive to acetaminophen toxicosis
They are deficient in glucouronyl transferase & therefore have limited capacity to glucouronidate this drugs
At what mg/kg will acetaminophen toxicity occur in dogs? What about cats
- Cats: 10 - 40 mg/kg
- Dogs: >100 mg/kg
What do cats develop when they experience acetaminophen toxicity
Primarily dev methemoglobinemia within a few hours followed by heinz body formation
What are the signs of acetaminophen toxicity in cats
- Methemoglobinemia makes mucous membranes brown or muddy in color
- Tachycardia
- Hyperpnea
- Weakness
- Lethargy
- Depression
- Weakness
- Hyperventilation
- Icterus
- Vomiting
- Hypothermia
- Facial or paw edema
- Cyanosis
- Dyspnea
- Hepatic necrosis
- Death
Describe Dipyrone (AKA Metamizole)
- Atypical NSAID
- Weak COX-1 & COX-2 inhibition
- COX-3?
- FDA approved for use in horses but use has been described in several vet species
- Use caution in px w/ comorbidities
Describe Flunixin meglumine
- Non-selective NSAID
- FDA approved for tx of inflammation * fever in food animals
- Most commonly used NSAID for tx of colic & assoc endotoxemia in horses
- Comes in an oral paste & injectable formula
- Do not admin IM
Describe Phyenylbutazone
- Non-selective NSAID
- Used to treat musculoskeletal pain & inflammation in horses
- Prohibited from use in dairy cattle (females > 20 M of age
What are the side effects of Phenylbutazone
- Gastric ulceration
- Renal necrosis
- Anemia
What can happen if PBZ is admin to horses
Right dorsal colitis
What is the most common problem associated w/ the use of NSAIDs
- Inhibition of intestinal healing mechanisms
- Gastric ulceration
- Both caused by inhibition of endogenous PGs
What are signs of a GI side effect
- Depression
- Lethargy
- Inappetence
- Nausea
- Vomiting &/or diarrhea that may include blood
- An ulcer that could lead to perforation of the GI tract
(Behavior changes, eating less, skin redness/scabs, & Tarry stool/diarrhea/vomiting = BEST to remember)
What will the lab results show if the is a GI side effect caused by NSAIDs
- Decreased Hct & TP
- Increased BUN due to GI hemorrhage
- Elevated leukocyte count
What are the renal side effects of NSAIDs
- Renal dysfundction may occur b/c of PG inhibition
- During normovolemia there is little need for production of PG
- Hypovolemia causes an increase in PG production & is important for maintaining renal perfusion
- Effects the decision of when to admin an NSAID perioperatively
What causes renal failure when giving NSAIDs
Inhibition of COX enzymes can result in vasoconstriction of afferent & efferent blood vessels, glomerular dysfunction, & abnormal tubuloglomerular feedback
What should be done if a px is dehydrated or hypovolemic
Hold off on giving NSAID until underlying prob is corrected
What should be done if there is a concern that the px may become hypotensive during ax
- Do not give the NSAID until stable in recovery
- Institute corrective tx for hypotension promptly
What are the hepatic side effects of NSAIDs
- Carprofen associated w/ idiosyncratic hepatocellular necrosis
- Onset of signs seen by 21 days of use in affected dogs
- Anorexia, vomiting, icterus & increase in hepatic enzymes
- Most dogs recover if the meds are stopped & supportive care is fiven
- Liver fxn should be monitored w/ the use of all NSAIDs
What are the bone & cartilage effects of NSAIDs
- PGs play an important role in bone repair & norm bone homeostasis
- Small mammal models indicate that NSAIDs potentially alter bone healing (discontinuation = healing returns to norm)
- Experimental data suggests NSAIDs can slow the progression of OA
What effects do NSAIDs have on coagulation
- US NSAIDs that have been evaluated don’t have a significant clinical effect on bleeding time following periop admin
- Aspirin is the only drug of concern due to irreversible effect on platelet fxn that persists until the platelets are replaced (discontinue use 7 - 10 D prior to surgery)
Fill out the chart for Tx of NSAID toxicity
